CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells

Yu Tzu Tai, Ender Soydan, Weihua Song, Mariateresa Fulciniti, Kihyun Kim, Fangxin Hong, Xian Feng Li, Peter Burger, Matthew J. Rumizen, Sabikun Nahar, Klaus Podar, Teru Hideshima, Nikhil C. Munshi, Giovanni Tonon, Ruben D. Carrasco, Daniel E H Afar, Kenneth C. Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient seraandcorrelates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNAdecreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf-targeted cyclin D2-dependent proliferation, -integrin βl7/αE-mediated myeloma adhesion toBMSCs,and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

Original languageEnglish
Pages (from-to)4309-4318
Number of pages10
JournalBlood
Volume113
Issue number18
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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